Short and Scalable Total Synthesis of Myrioneuron Alkaloids (±)-α,β-Myrifabral A and B

Article abstract of DOI:10.1021/acs.orglett.6b00005

The first total synthesis of the Myrioneuron alkaloids (±)-α,β-myrifabral A and B has been accomplished in only four steps from conveniently available starting materials. This short synthesis relied on the use of a key tandem Mannich/amidation reaction to rapidly construct the core framework and two carbon stereocenters. The synthetic route allows for large scale preparation of these promising natural products against the hepatitis C virus (HCV). (Chemical Equation Presented).

Full text of DOI:10.1021/acs.orglett.6b00005

Letter
pubs.acs.org/OrgLett
Short and Scalable Total Synthesis of Myrioneuron Alkaloids ( )-α,β-
Myrifabral A and B
Dengpeng Song,† Zhengshen Wang,† Ruoming Mei,† Weiwei Zhang,† Donghui Ma,† Dengyu Xu,†
Xingang Xie,† and Xuegong She*,†,‡
†State Key Laboratory of Applied Organic Chemistry, Department of Chemistry, Lanzhou University, Lanzhou 730000, People’s
Republic of China
‡Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, People’s Republic of China
S
* Supporting Information
ABSTRACT: The first total synthesis of the Myrioneuron
alkaloids ( )-α,β-myrifabral A and B has been accomplished in
only four steps from conveniently available starting materials.
This short synthesis relied on the use of a key tandem
Mannich/amidation reaction to rapidly construct the core
framework and two carbon stereocenters. The synthetic route
allows for large scale preparation of these promising natural
products against the hepatitis C virus (HCV).
he Myrioneuron alkaloids (Figure 1) are a small but
growing group of plant metabolites that have a common
promising anti-HCV activity (IC50 0.9 to 4.7 μM) with
cytotoxicity lower than that of telaprevir, a commercial
pharmaceutical drug for the treatment of hepatitis C. In
consideration of their appealing architecture and significant
bioactive potential as lead compounds for the discovery of new
drugs, it is necessary to develop a short and scalable synthetic
route to ( )-α,β-myrifabral A and B for a further and detailed
structure−activity relationship (SAR) study. However, rela-
tively little study on the synthesis of the Myrioneuron alkaloids
has been accomplished at the present.3 Herein, we describe a
tandem Mannich/amidation reaction to efficiently establish all
of the carbons and molecule framework, and a concise total
synthesis of the targeted alkaloids in only four steps from
known iodide 9.
T
Our retrosynthetic analysis is shown in Scheme 1. α,β-
Myrifabral B could be derived from α,β-myrifabral A, which was
assumed to be constructed from tricyclic intermediate 5 via
several simple chemical transformations (reduction, deacetali-
zation, and hemiacetalization). Considering the biosynthesis of
these alkaloids from lysine, we reasoned that pivotal tricyclic
intermediate 5 could be obtained through a tandem Mannich/
amidation sequence from lysine derivative 6 and compound 7,
which was readily accessible from commercial available
compound 8 and known iodide 9 (Scheme 1).
As shown in Scheme 2, our synthesis commenced with the
known iodide 9, which was easily prepared in one step from
acrolein using Gil’s conditions.4 Then it was coupled with
commercial compound 8 to provide the required alkylative
product 7.5 The other required segment imine 6 was also
readily prepared from piperidine.6
Figure 1. Representative Myrioneuron alkaloids.
biosynthesis originating from lysine.1 Structurally, these
alkaloids share a cis-decahydroquinoline system that often
incorporates 1,3-oxazine and/or 1,3-diazine rings. In 2014, two
clusters including four new Myrioneuron alkaloids ( )-α,β-
myrifabral A (1 and 2) and B (3 and 4) were isolated by Hao
and co-workers from Myrioneuron faberi, which is a unique
plant mainly distributed in China.2 Unlike all previously known
Myrioneuron alkaloids, the four new members possess a novel
cyclohexane-fused octahydroquinolizine skeleton together with
a six-membered cyclic hemiacetal. Additionally, these natural
compounds contain four continuous chiral centers including a
quaternary stereocenter embedded in the bridgehead. Prelimi-
nary bioactivity test indicated that, even obtained as racemic
mixtures, both clusters and some derivatives presented
Received: January 2, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00005
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Retrosynthetic Analysis for ( )-α,β-Myrifabral A
and B
Table 1. Reaction Condition Survey for Tandem Mannich/
Amidation Reaction
a
c
entry
promoter
solvent
yield (%)
1
2
3
4
5
6
7
8
proline
CH3CN
n.d.
n.d.
46
b
LiCl/DBU
MeONa
MeONa
MeONa
p-TSA
DMF
MeOH
EtOH
17
i-PrOH
MeOH
t-BuOH
MeOH
trace
n.d.
n.d.
t-BuOK
MeONa
d
39
a
Unless otherwise specified, the reaction was carried out with 7 (1.0
mmol) and 6 (1.5 mmol) in the presence of promoter (2.0 mmol) and
b
solvent (2.0 mL) under reflux for 72 h. Reaction temperature is 100
c
d
°C. Isolated yields. Run on gram scale.
The completion of the total synthesis of ( )-α,β-myrifabral
A and B is depicted in Scheme 3. Deprotection of 10 with 2 N
Scheme 2. Preparation of Key Intermediate 10
Scheme 3. Synthesis of ( )-α,β-Myrifabral A and B
With segments 6 and 7 in hand, we subsequently investigated
the feasibility of the key tandem Mannich/amidation reaction.
As shown in Table 1, under organocatalyst or weak acid−base
pairs condition only provided a few unidentified compounds
(Table 1, entries 1−2). Brønsted acid was also ineffective with
only starting material recovered (Table 1, entry 6). To our
delight, the desired tricyclic 5 was obtained with 46% yield in
the presence of MeONa in MeOH under reflux for 72 h (Table
1, entry 3). Moreover, more hindered base and alcohols proved
to be invalid (Table 1, entries 4, 5, and 7). It is worth
mentioning that this procedure could be carried out on a large
scale (up to 5 g of 5 prepared per batch) with slightly reduced
yield (Table 1, entry 8) from relatively inexpensive staring
materials and the requisite piperidine ring together with two
new stereogenic centers were efficiently assembled in this one-
step operation.
After establishing the core framework of the targeted
alkaloids, we then attempted to reduce the two carbonyl
groups simultaneously. The carbonyl group at C12 of 5 was
anticipated to be stereoselectively reduced due to the steric
hindrance of the cyclohexane ring. As expected, we were
pleased to discover that reduction of 5 with LiAlH4 delivered a
6.75:1 mixture of two diastereomers and that the major product
10 could be reliably isolated in 81% yield.
HCl followed by spontaneous hemiacetalization smoothly
delivered ( )-α,β-myrifabral A as a cluster in 92% overall
yield, the synthesis was carried out on a multigram scale to
provide 2.1 g of cluster A. Interestingly, ( )-α-myrifabral A (1)
could be recrystallized from EtOAc solution of cluster A, and its
X-ray diffraction experiment was confirmed against the
structure information on ( )-α-myrifabral A (1) reported by
Hao and co-workers.
At last stage, transformation of ( )-α,β-myrifabral A to
( )-α,β-myrifabral B was investigated, formaldehyde and
diethylamine were added to the reaction mixture, but the
expected mannich reaction did not occurr under various
conditions such as numerous solvents (THF, MeOH, i-PrOH,
and H2O) and different acids (HCl, H2SO4, and H3PO4). We
postulated that the failure was attributed to the difficulty of
forming the requisite imine for the next Mannich reaction. To
overcome this obstacle, a labile aza-acetal 117 was used to in
situ generate the required imine intermediate. Gratifyingly,
B
DOI: 10.1021/acs.orglett.6b00005
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Chim. Acta 2009, 92, 98. (c) Monaco, M. R.; Renzi, P.; Scarpino
Schietroma, D. M.; Bella, M. Org. Lett. 2011, 13, 4546.
(7) (a) Stewart, T. D.; Aston, J. G. J. Am. Chem. Soc. 1926, 48, 1642.
(b) Sakai, N.; Shimamura, K.; Ikeda, R.; Konakahara, T. J. Org. Chem.
2010, 75, 3923.
(8) (a) Ooi, T.; Miki, T.; Taniguchi, M.; Shiraishi, M.; Takeuchi, M.;
Maruoka, K. Angew. Chem., Int. Ed. 2003, 42, 3796. (b) Wu, F.; Hong,
R.; Khan, J.; Liu, X.; Deng, L. Angew. Chem., Int. Ed. 2006, 45, 4301.
(c) Lathrop, S. P.; Rovis, T. J. Am. Chem. Soc. 2009, 131, 13628.
(d) Quintard, A.; Constantieux, T.; Rodriguez, J. Angew. Chem., Int. Ed.
2013, 52, 12883.
treatment of 10 with 2 N HCl in THF under reflux for 4 h
followed by slow addition of 11, we successfully obtained
( )-α,β-myrifabral B and ( )-α,β-myrifabral A with 42% (>500
mg scale) and 21% yield in one pot, respectively. The
spectroscopic data (1H and 13C NMR spectra and HRMS) of
synthetic clusters A and B were in good agreement with those
of the natural products.
In summary, we have accomplished the first total synthesis of
the anti-HCV natural products ( )-α,β-myrifabral A and B in
only four steps from conveniently available iodide 9. The
demonstrated short approach features a tandem Mannich/
amidation reaction for the construction of the core framework,
and a one pot deacetalization/Mannich reaction for the
synthesis of cluster B. In addition, our strategy should allow
asymmetric synthesis of these natural products, via an
enantioselective Michael conjugate addition of 8 followed by
selective protection of the aldehyde group according to the
previously described method.8 Notably, our route enables the
synthesis of significant quantities and should be helpful for
further SAR studies on natural Myrioneuron alkaloids and
analogues.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00005.
X-ray data for compound 1 (CIF)
Detailed experimental procedures and full spectroscopic
data for all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: shexg@lzu.edu.cn. Fax: +86-931-8912582.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Science Foundation
of China (21125207, 21372103, 21472079, and 21572088),
SRFDP (20130211110018), and IRT_15R28.
REFERENCES
■
(1) (a) Gravel, E.; Poupon, E. Nat. Prod. Rep. 2010, 27, 32.
(b) Poupon, E.; Gravel, E. Chem. - Eur. J. 2015, 21, 10604.
(2) Cao, M.-M.; Zhang, Y.; Li, X.-H.; Peng, Z.-G.; Jiang, J.-D.; Gu, Y.-
C.; Di, Y.-T.; Li, X.-N.; Chen, D.-Z.; Xia, C.-F.; He, H.-P.; Li, S.-L.;
Hao, X.-J. J. Org. Chem. 2014, 79, 7945.
(3) (a) Pham, V. C.; Jossang, A.; Chiaroni, A.; Sev
Tetrahedron Lett. 2002, 43, 7565. (b) Pham, V. C.; Jossang, A.;
Chiaroni, A.; Sevenet, T.; Nguyen, V. H.; Bodo, B. Org. Lett. 2007, 9,
3531. (c) Pham, V. C.; Jossang, A.; Grellier, P.; Sevenet, T.; Nguyen,
́
enet, T.; Bodo, B.
́
́
V. H.; Bodo, B. J. Org. Chem. 2008, 73, 7565. (d) Burrell, A. J. M.;
Coldham, I.; Oram, N. Org. Lett. 2009, 11, 1515. (e) Burrell, A. J. M.;
Coldham, I.; Watson, L.; Oram, N.; Pilgram, C. D.; Martin, N. G. J.
Org. Chem. 2009, 74, 2290. (f) Nocket, A. J.; Weinreb, S. M. Angew.
Chem., Int. Ed. 2014, 53, 14162. (g) Nocket, A. J.; Feng, Y.; Weinreb,
S. M. J. Org. Chem. 2015, 80, 1116.
(4) Gil, G. Tetrahedron Lett. 1984, 25, 3805.
(5) Ito, H.; Ohmiya, H.; Sawamura, M. Org. Lett. 2010, 12, 4380.
(6) (a) Rouchaud, A.; Braekman, J.-C. Eur. J. Org. Chem. 2009, 2009,
2666. (b) Darwich, C.; Elkhatib, M.; Steinhauser, G.; Delalu, H. Helv.
C
DOI: 10.1021/acs.orglett.6b00005
Org. Lett. XXXX, XXX, XXX−XXX